Dengue viruses are found in over 100 countries and cause the tropical disease known as dengue fever. Dengue viruses affect around 100 million people per year and can – in severe cases – lead to death. Unlike many other deadly diseases, there is currently no vaccine that completely prevents dengue fever.

It is thought that dengue viruses that circulate in human populations were derived from monkey versions of that same virus. However, research suggests that both human and primate variations of dengue viruses appear to multiply much better in humans than in other species. Scientists believe that this is because some animals, including primates, have defense mechanisms that are ineffective in humans.

To explore this idea, Stabell et al. looked at a protein called STING in humans and in three different primates: the chimpanzee, the rhesus macaque, and the common marmoset. STING plays an important role in the immune system and helps to fight infections caused by viruses and other microbes.

During replication – the process by which a virus spreads through an organism’s cells – the dengue virus cuts and inactivates the human STING protein, and so helps the virus spread. Stabell et al. discovered that in most primates, dengue viruses cannot inactivate STING. This was found to be reliant on a small region in the STING protein that differed between humans and primates. This small difference may, in part, explain why dengue viruses replicate better in humans than other primates.

Stabell et al. then searched for other animals whose STING protein would be susceptible to dengue virus inactivation. Using a database with genetic information of over 5,000 mammals, Stabell et al. identified STING proteins of three types of apes and three types of rodents that could also be deactivated by dengue viruses.

To develop a vaccine or antiviral drug scientists generally need to study the disease in living animals. Since dengue viruses replicate more successfully in humans than they do in other animal models, it makes it more challenging to find an effective treatment. The results from Stabell et al. may help to identify animals that could be strong candidates for future research into dengue viruses, potentially paving the way for further therapeutic development.

Dengue viruses cause clinical disease in approximately 100 million individuals each year and are found in over 100 countries (Bhatt et al., 2013). Yet, to date no vaccine exists that conveys cross-protection against all human dengue viruses (Scherwitzl et al., 2017). Dengue viruses are positive sense RNA viruses in the family Flaviviridae, and are related to yellow fever virus, Zika virus, and West Nile virus (Best, 2016). These viruses are primarily transmitted between humans in highly populated areas by Aedes aegypti and Aedes albopictus mosquitoes, in what are referred to as human (or ‘urban’) transmission cycles (Diamond and Pierson, 2015; Hanley et al., 2013; Vasilakis et al., 2011). Sylvatic (i.e. forest) dengue virus transmission cycles, which are separate from the human transmission cycles, exist in Asia and Africa and involve nonhuman primates and forest-dwelling Aedes mosquitos (Vasilakis et al., 2011; Wang et al., 2000; Rico-Hesse, 1990). While the exact nonhuman primate species that serve as the sustaining natural reservoirs for sylvatic dengue viruses are unknown, the global distribution of both dengue viruses and their transmitting mosquitoes could be consistent with a significant number of primate species being involved (Figure 1—figure supplement 1) (Hanley et al., 2013; Vasilakis et al., 2011). Primarily, dengue viruses have been associated with monkeys (rather than apes) found in Africa and Asia (Figure 1). Human dengue viruses cluster into four phylogenetically distinct clades referred to as DENV1, 2, 3, and 4 (Vasilakis and Weaver, 2008). These clades have sylvatic dengue virus isolates at their bases, supporting zoonotic origins of the four dengue viruses that now circulate in humans (Wang et al., 2000; Pyke et al., 2016; Weaver and Vasilakis, 2009). Human dengue viruses have now become uncoupled from the sylvatic reservoir and require only humans and mosquitoes to be sustained (Mayer et al., 2017).

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In side-by-side experiments, sylvatic and human dengue viruses replicate similarly in human cells (Vasilakis et al., 2007; Vasilakis et al., 2008). These results have been interpreted to mean that there is little or no adaptive barrier for the emergence of sylvatic dengue viruses into human populations, and the view that dengue viruses are generalists capable of infecting a wide range of primate species including humans. Thus, a paradox exists in understanding why human dengue viruses are so difficult to model in nonhuman primates. Chimpanzees (Pan troglodytes) (Scherer et al., 1978), rhesus macaques (Macaca mulatta) (Halstead et al., 1973; Hickey et al., 2013), marmosets (multiple Callithrix species) (Moi et al., 2013; Ferreira et al., 2014), and other nonhuman primate species (Althouse et al., 2014) have been explored as possible primate models for studying dengue virus pathogenesis and for vaccine challenge. In general, it has been observed that dengue does not replicate to high titers in these models, and little or no overt disease pathology is observed (Cassetti et al., 2010; Zompi and Harris, 2012). If human and sylvatic viruses are the same in their properties, we speculated that there must instead be something special about the replication of these viruses in the human host.

STING is a multi-pass transmembrane protein found in the endoplasmic reticulum, and functions as a critical component in the innate immune sensing pathway for intracellular pathogens (Ishikawa and Barber, 2008; Zhong et al., 2008; Ishikawa et al., 2009; Jin et al., 2008; Sun et al., 2009; Burdette and Vance, 2013). Although originally described as part of the response to cytosolic DNA sensing (Zhang et al., 2011), STING is also activated upon RNA virus infection (Holm et al., 2016). Underscoring this, several RNA viruses encode proteins that antagonize or degrade STING (Sun et al., 2012; Nitta et al., 2013; Ding et al., 2013; Aguirre et al., 2012; Yu et al., 2012). For instance, the NS2B3 protease of one human dengue virus, DENV2, has been shown to target human STING for cleavage (Aguirre et al., 2012; Yu et al., 2012). Through the cleavage of STING, DENV2 renders the host unable to induce the phosphorylation of Interferon Regulatory Factor 3 (IRF3), therefore decreasing production of type I interferon and increasing viral titers (Green et al., 2014). Mouse STING is resistant to cleavage by the DENV2 protease (Aguirre et al., 2012; Yu et al., 2012). This at least partially explains why mice mount an effective immune response against dengue viruses, protecting them against infection and compromising their utility as model organisms (Cassetti et al., 2010; Zompi and Harris, 2012; Ashour et al., 2010). Dengue viruses are known to mute the host interferon response in other ways as well, with the other predominant mechanism being the degradation of STAT2 (Ashour et al., 2009; Jones et al., 2005; Mazzon et al., 2009; Best, 2017; Morrison et al., 2012).

In this study, we show that the NS2B3 proteases of human (DENV1-4) and sylvatic dengue viruses universally cleave human STING. However, none of these proteases can cleave the STING proteins of chimpanzees, macaques, or marmosets, three primate species that have been pursued as model organisms. We show that an ‘RG’ motif at positions 78/79 of STING is critical for susceptibility to cleavage, and conversion of these residues to ‘RG’ renders all nonhuman primate STING proteins tested, as well as mouse STING, sensitive to dengue virus proteases. Out of the entire Genbank database, along with our sequencing of STING from 16 additional primate species, we identify only a small number of apes (gorillas, orangutans, and gibbons), and three small rodent species (chinchillas, naked mole rats, and desert woodrats) as encoding a functional dengue virus cleavage determinant in STING. This may, in part, explain why modeling dengue virus in animal models has been so difficult.

In humans cells, sylvatic and human dengue viruses replicate similarly (Vasilakis et al., 2007, 2008). These results have been interpreted to mean that there is little or no adaptive barrier for the emergence of sylvatic dengue viruses into human populations. Our data agree with, but add a new element to, this model. Rather than there being critical differences between human and sylvatic viruses, our data suggest that there are critical differences between human and monkey hosts. This difference tracks, at least in part, to STING, revealing one way in which dengue viruses are reaching higher titers in humans than in monkey models. Collectively our data suggest that all dengue viruses cleave human STING, but not the versions of STING found in most other mammals. We have used the STING proteins of closely related primate species to map the determinant of cleavage in STING. We find that the viral protease is recognizing (i.e. cutting or binding) residues around positions 78/79 of STING. We show that an ‘RG’ motif at these two residues is necessary and sufficient for cleavage by the proteases of all four human epidemic dengue viruses, and one sylvatic dengue virus. Yet, only some apes and three rodent species, out of all of the mammalian STING sequences in Genbank, encode an RG at positions 78/79.

Why do dengue viruses universally cleave human but not monkey STING? It’s possible that what we have uncovered is a brilliant method for balancing alternate host species, one of which is dense and abundant (humans), versus others that are spare and exist in smaller populations (primates in nature). In this scenario, dengue viruses have evolved to suppress innate immunity in humans in order to increase viral titers and spread, even though this trait comes at the cost of increased pathogenicity in some individuals. This might be a good strategy in our abundant and dense host population, where the fitness cost of severe disease in a fraction of individuals would be outweighed by excellent spread. Remarkably, though, dengue viruses have achieved this by evolving to recognize a portion of human STING that is not conserved in the STING of the wild and more rare animals that serve as their sustaining reservoir in nature, allowing the viruses to maintain decreased pathogenicity in these species. The evolution of the viral proteases to cleave human STING and simultaneously to avoid cleavage of monkey STING would be expected to reduce virus titers in monkeys, as the interferon pathway would be at least partially enabled. This may be beneficial for many reasons, one of which is that the production of a low-level innate immune response may allow the virus to replicate in reservoir host species without inducing high titers and strong adaptive immune responses. Alternately, a second possibility is that sylvatic dengue viruses do cleave the STING of monkeys, but that the sylvatic virus (DakAr-141069) that we tested is not representative. However, we find this unlikely. Because DENV1-4 also cannot cleave monkey STING, and all derive from the sylvatic reservoir, this supports the finding that sylvatic viruses do not cleave monkey STING. Third, a final possibility is that apes are critical reservoirs for dengue viruses in nature. Gorillas encode ‘RG’ at 78/79 and are found in Africa, while orangutans and gibbons are found in Asia and also encode the correct cleavage motif for the dengue virus protease. In fact, wild orangutans have previously been found to have neutralizing antibodies against dengue virus (Wolfe et al., 2001). While apes could be playing a role as sylvatic hosts, the highly endangered and rare status of most apes makes it hard to believe that they are playing a major role in sustaining sylvatic dengue virus currently (Geissmann, 2007; Walsh et al., 2003).

The specific primate species that serve as the sustaining reservoir for sylvatic dengue viruses in nature are unknown (Vasilakis et al., 2011). Various Old World monkey species in both Asia and Africa are suspected hosts (Vasilakis et al., 2011; Rodhain, 1991; Diallo et al., 2003). For instance, sylvatic dengue viruses have been isolated directly from macaques (Macaca fascicularis) and leaf monkeys (Presbytis obscura) that were placed as sentinels in forest canopies (Rudnick, 1986). Other primates have been shown to have antibodies to dengue virus, including macaques (Macaca fascicularis and Macaca nemestrina), leaf monkeys (Presbytis cristata) (Rudnick, 1965), African green monkeys (Chlorocebus sabaeus) (Diallo et al., 2003), and one ape species, the Bornean orangutan (Pongo pygmaeus) (Wolfe et al., 2001). But these results are not definitive due to the cross-reactivity of antibodies directed against various flaviviruses (Calisher et al., 1989; Tesh et al., 2002; Mansfield et al., 2011), and the possibility that some primates might be accidental, rather than sustaining reservoir hosts (Vasilakis et al., 2011). Instead of being directly isolated from primates, most sylvatic dengue viruses have been obtained from forest mosquitoes (Diallo et al., 2003; Rudnick, 1986), or from humans that contracted the virus in the forest (Pyke et al., 2016; Cardosa et al., 2009; Franco et al., 2011). Therefore, there are many deficiencies in our understanding of the natural reservoir for dengue viruses. Interestingly, though, we have not identified any monkey species with an ‘RG’ at positions 78/79 in STING. Our results would indicate that dengue viruses, in general, cannot cleave the STING of monkey hosts. Our data suggests that even a sylvatic dengue virus, which we find targets the same residues in STING, would not be able to cleave STING of monkeys.

There are also implications of these findings to our understanding of dengue virus model organisms. If dengue proteases do not cleave most nonhuman forms of STING, this may at least partially explain why it has been so difficult to model dengue infection in immune-competent animals. Nonhuman primates infected with dengue virus generally don’t develop clinical signs of disease, consistent with enhanced control of the virus compared to humans (Cassetti et al., 2010). In fact, when human dengue viruses have been observed to replicate robustly in primate cell lines, these experiments have typically been done in cells such as Vero (Vasilakis et al., 2008; Rossi et al., 2012; Vasilakis et al., 2009) which are deficient in the type I interferon response (Osada et al., 2014; Desmyter et al., 1968). Human dengue viruses also cannot cleave mouse STING ((Aguirre et al., 2012; Yu et al., 2012) and herein), consistent with the heightened control of this virus in mice as well (Cassetti et al., 2010). Dengue virus will replicate to high titers in mice lacking key genes important for the interferon response, but for many reasons it is desirable to develop animal models in immune competent hosts (Cassetti et al., 2010). STING now adds to a growing list of host proteins that regulate viral infection differently even in closely related host species (for example, [Stabell et al., 2016; Lou et al., 2016; Rowley et al., 2016; Kerr et al., 2015; Meyerson et al., 2015; Demogines et al., 2012; Stremlau et al., 2004; Demogines et al., 2013; Ng et al., 2015; Hueffer et al., 2003; Radoshitzky et al., 2008; Patel et al., 2012; Elde et al., 2009; Martin et al., 2013; Miller et al., 2012; Sawyer and Elde, 2012; Meyerson et al., 2017]). The identification of such genes is critical to our understanding of viral adaptation during host switching, and to the development of animal models in which to study human viruses.

It is possible that the identification of small mammals that have a cleavage-susceptible STING would facilitate the development of better animal models for studying dengue virus. Our work suggests the identity of three such species: the naked mole rat, the common chinchilla, and the desert woodrat. All three of these small rodents are already used as animal models in biomedical research, and the genomes of all three have been sequenced (Keane et al., 2014; Nathaniel et al., 2013; Shimoyama et al., 2016; Campbell et al., 2016; Skopec et al., 2013). These species could be superior to STING knockout mice, in that the STING pathway would be intact and the cleavage of STING by the virus would be naturally modeled rather than just bypassed. These species may also be superior to future models where mouse (Mus musculus) STING would be replaced with human STING in transgenic animals. In this case, it is unknown if human STING would perform all of its functions the same in mouse as it does in humans. The advantage of using a rodent model with a STING that is naturally susceptible to dengue virus cleavage would be that the STING pathways would all be fully functional and intact. It is important to point out that, in addition to cleaving STING, dengue viruses modulate the interferon response in other ways as well. For instance, dengue viruses also bypass the type I interferon response by binding and degrading host STAT2 via the viral NS5 protein (Ashour et al., 2009; Jones et al., 2005; Mazzon et al., 2009; Best, 2017). Ideally, human dengue viruses would also be able to bind and degrade STAT2 in newly developed models, as they do in humans. Further, dengue viruses neutralize both the type I and type II interferon responses in other ways as well (Perry et al., 2011; Shresta et al., 2004; Aguirre et al., 2017; Aguirre and Fernandez-Sesma, 2017). Other known host-virus interactions would also need to be characterized in any potential new model organism.

It is notable that chimpanzees and bonobos encode STINGs that are resistant to cleavage, while STINGs of all other apes are susceptible. These two species differ from other apes in encoding a ‘WG’ at 78/79 of STING rather than the ‘RG’ encoded by all other apes (Figure 6). Remarkably, it was previously found that the ‘W’ at position 78, destroying the dengue cleavage determinant, was fixed by positive natural selection in wild chimpanzee populations (Mozzi et al., 2015). Chimpanzees are not one of the suspected natural reservoirs of dengue virus, but chimpanzee ranges do co-occur with known human outbreaks and with sylvatic cycles (Figure 1—figure supplement 1). One model is that, as dengue virus spread through Africa, a SNP in chimpanzee STING (or the STING of the chimpanzee/bonobo ancestor) at position 78 started to experience strong selection because it provided protection against cleavage by dengue viruses. This would have driven a selective sweep in chimpanzee populations, causing this species to become less susceptible to viral infection. It has previously been proposed that evolutionary pressure imposed by flavivirus proteases can drive selection at cleavage sites. For examples, the hepatitis C protease cleaves MAVS, another host signaling protein in the interferon induction cascade (Li et al., 2005b; Meylan et al., 2005). MAVS has experienced positive selection at a residue in the cleavage site for the hepatitis C virus protease (Patel et al., 2012). The authors of this study speculated that ancient viruses may have exerted selective pressure on primate genomes to acquire mutations in the cleavage site.

Like other viruses, dengue viruses remodel their host cellular environment in numerous ways, including the cleavage of STING and degradation of STAT2. Using the rich information that exists on how dengue viruses accomplish this, the genetic susceptibility of both suspected reservoir hosts, and potential new animal models, can be systematically assessed. Characterizing how host-virus interactions play out uniquely in different host species will help us to understand dengue virus in critical ways. For instance, it will reveal how dengue viruses do (or do not) need to evolve their genomes as they transmit to humans from nonhuman primates in nature. Also, understanding the genetics of host tropism will help identify better laboratory animals that can be used to study dengue virus pathogenesis and to develop drugs and vaccines.

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Author details

1. Alex C Stabell

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—original draft

   Competing interests

   No competing interests declared

2. Nicholas R Meyerson

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Validation, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

3. Rebekah C Gullberg

   Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, United States

   Contribution

   Validation, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

4. Alison R Gilchrist

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Kristofor J Webb

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

6. William M Old

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Formal analysis, Supervision

   Competing interests

   No competing interests declared

7. Rushika Perera

   Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, United States

   Contribution

   Validation, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

8. Sara L Sawyer

   Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Writing—review and editing

   For correspondence

   ssawyer@colorado.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6965-1085

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